Visible-Light-Mediated Ring-Opening Geminal Dibromination of Alkenes via Alkoxy Radicals Enabled by Electron Donor–Acceptor Complex

An electron donor–acceptor complex was utilized to generate alkoxy radicals from alcohols under mild conditions using visible light. This approach was combined with a hydroxybromination process to achieve the deconstructive functionalization of alkenes, leading to the production of geminal dibromides. Mechanistic investigations indicated the intermediacy of hypervalent iodine (III) compounds.


Introduction
In organic photochemistry, electron donor-acceptor (EDA) complexes play an important role in facilitating photochemical reactions [1,2].When an electron donor and acceptor form a complex, they can absorb visible light and undergo single-electron transfer (SET).Despite being unable to absorb visible light individually, EDA complexes create radical intermediates to participate in subsequent reactions.Electron donor-acceptor (EDA) complexes in photochemistry offer a cost-effective alternative to obtain target chemical structures without relying on expensive photocatalysts [3][4][5][6].Despite significant progress made in recent years regarding the potential of EDA complexes in synthetic methods [7][8][9][10][11][12][13][14][15][16][17], further exploration of the diversity in EDA complexes is needed to fully realize the potential of this approach for manipulating radical chemistry.Expanding the range of EDA complexes could open up broader prospects in this field.
Alkoxy radicals are highly reactive open-shell species that are utilized as crucial intermediates in various synthetic strategies [18][19][20][21].However, generating alkoxy radicals from alcohols under mild conditions remains challenging and continues to attract the attention of researchers [22][23][24][25][26][27][28].Recent developments in photochemistry have made it possible to convert free alcohols to alkoxy radicals under mild conditions [29][30][31][32][33][34][35][36][37][38][39].Previous reports have shown that hypervalent iodine (III) compounds can facilitate the in situ formation of O-I (III) intermediates that can be easily cleaved to produce alkoxy radicals via single-electron oxidation or reduction by photocatalysts or direct photoexcitation, resulting in the homolysis of O-I bonds [40][41][42][43] (Figure 1a,b).In this study, we developed a method for the visible-light-promoted generation of alkoxy radicals using a donor-acceptor complex, which was used to achieve the ring-opening geminal debromination of alkenes.Alkene 1 first reacted with NBS in the presence of H 2 O, forming a hydroxybromation adduct in situ, which was converted to an alkoxy radical via the EDA complex in the reaction mixture.
The subsequent β-scission process could provide a ring-opening process, resulting in the final product 2 [44] (Figure 1c).kenes.Alkene 1 first reacted with NBS in the presence of H2O, forming a hydroxybromation adduct in situ, which was converted to an alkoxy radical via the EDA complex in the reaction mixture.The subsequent β-scission process could provide a ring-opening process, resulting in the final product 2 [44] (Figure 1c).

Results and Discussion
Our investigation began with the use of iodine (III) benziodoxole precursor 3 with commercially available N-bromoimides (N-bromosuccinimide 4 and N-bromophthalimide 5).Upon mixing 3 with N-bromosuccinimide or N-bromophthalimide, the UV/vis absorption spectrum of the mixture showed significant red-shifts (Figure 2a).A Job plot was also performed to confirm the formation of the donor-acceptor complex in the mixture (Figure 2b) [9].Subsequently, when iodine (III) benziodoxole 3 and 5 were exposed to blue light, the ring-opening product 2a was obtained in a 66% yield (Figure 2c).In this process, the EDA complex was photoactivated by blue light, and an intracomplex single-electron transfer (SET) afforded the radical ion pair.Then, by facilitating the irreversible cleavage of the O-I bond, the radical ion pair released the alkoxy radical, avoiding the back electron transfer (BET) process.Additionally, the by-product 6 was detected in the reaction mixture and could be isolated in a 20% yield, likely produced from the BI+ species during the reaction process.Previous reports have shown that BI-OR species can react with photocatalysts via a single-electron transfer (SET) process, generating the corresponding oxy radical and BI+ in reactions.Specifically, BI-OR species have been reported to undergo single-electron oxidation in reactions [32,33,35].These observations, along with previous reports, suggest that N-bromophthalimide may act as the electron acceptor in this case, with compound 3 serving as the electron donor.This is consistent with previous studies on similar iodine (III) species [32][33][34][35][45][46][47][48].
We then applied this method of alkoxy radical generation to the cascade ring-opening geminal dibromination reaction.Phenyl-1-cyclohexene 1a was selected as a representative model substrate and reacted as hypothesized.In order to raise the yield of product 2a, various modifications were tested (Table 1).Using an excess of the hypervalent iodine reagent to generate the BI-OR intermediate showed good results.When 1.5 equiv of BIOAc was added to the reaction mixture, 2a was obtained in a 39% yield.The usage of 2 equiv of BIOAc led to a good yield of 54%.Using NBS as a cheaper alternative in the reaction process, the corresponding product was obtained in a similar yield of 52%.Without a cooling fan, the reaction temperature was raised to 50 °C, which led to a higher yield of 76%.Changing the solvent from MeCN to DCM, PhCl, Acetone, THF, or EtOAc had no positive effect on the yield of the target product.Finally, prolonging the reaction time to

Results and Discussion
Our investigation began with the use of iodine (III) benziodoxole precursor 3 with commercially available N-bromoimides (N-bromosuccinimide 4 and N-bromophthalimide 5).Upon mixing 3 with N-bromosuccinimide or N-bromophthalimide, the UV/vis absorption spectrum of the mixture showed significant red-shifts (Figure 2a).A Job plot was also performed to confirm the formation of the donor-acceptor complex in the mixture (Figure 2b) [9].Subsequently, when iodine (III) benziodoxole 3 and 5 were exposed to blue light, the ring-opening product 2a was obtained in a 66% yield (Figure 2c).In this process, the EDA complex was photoactivated by blue light, and an intracomplex single-electron transfer (SET) afforded the radical ion pair.Then, by facilitating the irreversible cleavage of the O-I bond, the radical ion pair released the alkoxy radical, avoiding the back electron transfer (BET) process.Additionally, the by-product 6 was detected in the reaction mixture and could be isolated in a 20% yield, likely produced from the BI+ species during the reaction process.Previous reports have shown that BI-OR species can react with photocatalysts via a single-electron transfer (SET) process, generating the corresponding oxy radical and BI+ in reactions.Specifically, BI-OR species have been reported to undergo single-electron oxidation in reactions [32,33,35].These observations, along with previous reports, suggest that N-bromophthalimide may act as the electron acceptor in this case, with compound 3 serving as the electron donor.This is consistent with previous studies on similar iodine (III) species [32][33][34][35][45][46][47][48].
We then applied this method of alkoxy radical generation to the cascade ring-opening geminal dibromination reaction.Phenyl-1-cyclohexene 1a was selected as a representative model substrate and reacted as hypothesized.In order to raise the yield of product 2a, various modifications were tested (Table 1).Using an excess of the hypervalent iodine reagent to generate the BI-OR intermediate showed good results.When 1.5 equiv of BIOAc was added to the reaction mixture, 2a was obtained in a 39% yield.The usage of 2 equiv of BIOAc led to a good yield of 54%.Using NBS as a cheaper alternative in the reaction process, the corresponding product was obtained in a similar yield of 52%.Without a cooling fan, the reaction temperature was raised to 50 • C, which led to a higher yield of 76%.Changing the solvent from MeCN to DCM, PhCl, Acetone, THF, or EtOAc had no positive effect on the yield of the target product.Finally, prolonging the reaction time to 36 h gave a yield of 83%, and the control experiment confirmed that light irradiation was essential for this process.   2 MeCN 50 ND 1 Reaction conditions: 1a (0.2 mmol), 5 (0.44 mmol), H2O (10 mmol), solvent (2 mL), under argon, h. 2 NBS (0.44 mmol) was used instead of 5. 3 Reaction time was 36 h. 4 No light irradiation.Table 1.Optimization of the ring-opening geminal dibromination 1 .
Molecules 2024, 29, x FOR PEER REVIEW 3 of 36 h gave a yield of 83%, and the control experiment confirmed that light irradiation was essential for this process.With the optimized reaction conditions in hand, the substrate scope of this ringopening geminal dibromination was investigated.In this context, a variety of cyclohexene derivatives were applied.As shown in Figure 3, the aryl group functionality was examined, and all reactions proceeded well, resulting in the corresponding product 2a-h in moderateto-good yields.Products 2b-f contained aryl rings with varying electronic groups in the para-positions that were tolerant in the reaction process and gave a moderate-to-good yield of 60-84%.Products 2c and 2d, containing electron-donating groups, could be isolated in higher yields as compared to 2e, which contained electron-withdrawing groups.As product 2b contained a methoxy group within the structure, an aryl group bromination by-product was also detected [49][50][51], resulting in a lower yield in comparison to other substrates.Cyclohexenes 2 with substituents on the meta-positions of the phenyl group were also examined, affording target products in good yields.Then, various substituents on the cyclohexene rings were also studied with no drastic differences in the yield for products 2h-j.The cyclohexene rings were modified with methyl, ethyl, and difluoro groups (2h-j), and the results indicated that neither electronic nor steric effects had a significant influence on the procedure.
With the optimized reaction conditions in hand, the substrate scope of this ring-opening geminal dibromination was investigated.In this context, a variety of cyclohexene derivatives were applied.As shown in Figure 3, the aryl group functionality was examined, and all reactions proceeded well, resulting in the corresponding product 2a-h in moderate-to-good yields.Products 2b-f contained aryl rings with varying electronic groups in the para-positions that were tolerant in the reaction process and gave a moderate-to-good yield of 60-84%.Products 2c and 2d, containing electron-donating groups, could be isolated in higher yields as compared to 2e, which contained electron-withdrawing groups.As product 2b contained a methoxy group within the structure, an aryl group bromination by-product was also detected [49][50][51], resulting in a lower yield in comparison to other substrates.Cyclohexenes 2 with substituents on the meta-positions of the phenyl group were also examined, affording target products in good yields.Then, various substituents on the cyclohexene rings were also studied with no drastic differences in the yield for products 2h-j.The cyclohexene rings were modified with methyl, ethyl, and difluoro groups (2h-j), and the results indicated that neither electronic nor steric effects had a significant influence on the procedure.Apart from using cyclohexene derivatives, we also studied the productivity of this method with cyclopentene derivatives containing various functional groups on the aryl rings, as shown in Figure 3b,c.The corresponding products 7a-d were obtained in 69-80% yields.Moreover, this method was further examined with acyclic trisubstituted alkenes, which were transformed to the ketone 8a and 8b successfully by β-scission [29,52].
To gain mechanistic insight, we used bromohydrin 9 under standard conditions, which led to the formation of 2a [53].No target product was obtained in the presence of TEMPO, implying that a radical step might have been involved in the reaction mechanism.Neither 1a nor 9 could be converted to 2a in the absence of BI-OAc.The results of the on-off experiment are shown in Figure 4b.When the light was switched off, the formation of 2a immediately stopped.Conversely, the conversion from 1a to 2a resumed upon turning on the light, which excluded the possibility of a radical chain process in this reaction.
Apart from using cyclohexene derivatives, we also studied the productivity of this method with cyclopentene derivatives containing various functional groups on the aryl rings, as shown in Figure 3b,c.The corresponding products 7a-d were obtained in 69-80% yields.Moreover, this method was further examined with acyclic trisubstituted alkenes, which were transformed to the ketone 8a and 8b successfully by β-scission [29,52].
To gain mechanistic insight, we used bromohydrin 9 under standard conditions, which led to the formation of 2a [53].No target product was obtained in the presence of TEMPO, implying that a radical step might have been involved in the reaction mechanism.Neither 1a nor 9 could be converted to 2a in the absence of BI-OAc.The results of the on-off experiment are shown in Figure 4b.When the light was switched off, the formation of 2a immediately stopped.Conversely, the conversion from 1a to 2a resumed upon turning on the light, which excluded the possibility of a radical chain process in this reaction.

General Information
Unless otherwise noted, all chemicals were purchased from commercial suppliers (Sigma Aldrich (St. Louis, MO, USA), TCI (Toyko, Japan), Oakwood (West Columbia, SC, USA)) and used without further purification.When required, solvents were dried according to general purification methods.Two Kessil PR160 blue LED lamps (40 W), purchased from Kessil (Richmond, VA, USA), were used as the light source.The Emission profile of the Kessil PR160 blue LED lamps used to irradiate the reaction mixture is shown in Figure S2.The product mixtures were analyzed by thin-layer chromatography using TLC silica gel plates (Merck-Schuchardt, Hohenbrunn, Germany) with a fluorescent indicator (λ = 254 nm).The purification of the products was performed by flash column chromatography using silica gel 60 (63-200 µm) from SANPONT (Shanghai, China).NMR spectra were recorded on a Bruker AV-III400 (400 MHZ) or AMX500 (500 MHz) spectrometer (Karlsruhe, Germany) in deuterated solvents.Chemical shifts (δ) are reported in parts per million (ppm), and spin-spin coupling constants (J) are given in Hz, while multiplicities are given the standard abbreviations, s (singlet), d (doublet), t (triplet), q (quartet), br (broad), and m (multiplet).High-resolution mass spectra (HRMS) were recorded on a Finnigan/MAT 95XL-T spectrometer (San Jose, USA).The diastereomeric ratio (dr) was determined by 1H NMR of the crude product mixture.Absorption spectra were recorded in 1 cm path quartz cuvettes using an Edinburgh FS-5 spectrofluorometer (Livingston, UK).

General Information
Unless otherwise noted, all chemicals were purchased from commercial suppliers (Sigma Aldrich (St. Louis, MO, USA), TCI (Toyko, Japan), Oakwood (West Columbia, SC, USA)) and used without further purification.When required, solvents were dried according to general purification methods.Two Kessil PR160 blue LED lamps (40 W), purchased from Kessil (Richmond, VA, USA), were used as the light source.The Emission profile of the Kessil PR160 blue LED lamps used to irradiate the reaction mixture is shown in Figure S2.The product mixtures were analyzed by thin-layer chromatography using TLC silica gel plates (Merck-Schuchardt, Hohenbrunn, Germany) with a fluorescent indicator (λ = 254 nm).The purification of the products was performed by flash column chromatography using silica gel 60 (63-200 µm) from SANPONT (Shanghai, China).NMR spectra were recorded on a Bruker AV-III400 (400 MHZ) or AMX500 (500 MHz) spectrometer (Karlsruhe, Germany) in deuterated solvents.Chemical shifts (δ) are reported in parts per million (ppm), and spin-spin coupling constants (J) are given in Hz, while multiplicities are given the standard abbreviations, s (singlet), d (doublet), t (triplet), q (quartet), br (broad), and m (multiplet).High-resolution mass spectra (HRMS) were recorded on a Finnigan/MAT 95XL-T spectrometer (San Jose, CA, USA).The diastereomeric ratio (dr) was determined by 1H NMR of the crude product mixture.Absorption spectra were recorded in 1 cm path quartz cuvettes using an Edinburgh FS-5 spectrofluorometer (Livingston, UK).Continuous wave X-band ESR spectra were obtained with a JEOL (FA200) spectrometer (Toyko, Japan).

Conclusions
In summary, we have developed an EDA complex approach for preparing geminal dibromides from alkenes under mild conditions using visible light.Mechanistic studies suggest that the hypervalent iodine intermediate BI-OR, reacting as the electron donor for single-electron transfer, is crucial to the success of the reaction.

Supplementary Materials:
The following supporting information can be downloaded at https: //www.mdpi.com/article/10.3390/molecules29143281/s1.The following are available online:

Figure 1 .
Figure 1.Alkoxyl radical generation based on O-I bond.

Figure 1 .
Figure 1.Alkoxyl radical generation based on O-I bond.

Figure 2 .
Figure 2. EDA complex studies and reaction design.

a) UV-vis spectra for EDA complex 3 ,Figure 2 .
Figure 2. EDA complex studies and reaction design.

Figure 4 .
Figure 4. Control experiments and light on-off study.

Figure 4 .
Figure 4. Control experiments and light on-off study.